Psychological morbidity is a component of many physical diseases. Some behaviors that arise during the onset of an infectious illness or during flare-ups of a chronic inflammatory disease are phenotypically similar to those seen in depressive or anxiety reactions. A syndrome of sickness behaviors may exist that includes fatigue, somnolence, anorexia, decreased social and sexual behavior, and decreased novel stimulus exploration and locomotion. This syndrome is mediated by proinflammatory cytokines that are released into circulation after a systemic immune system challenge. Studies in sickness behavior have not yet included a detailed examination of the effect of cytokines on information processing ability, though cognitive disturbance is often cited as a likely component in the syndrome. From a public health perspective, cognitive disturbance during illness is extremely important because it can be among the most debilitating aspects of acute infections. From a behavioral medicine perspective, cognitive disturbance during flare-ups of chronic inflammatory diseases or during the course of cancer can complicate doctor-patient communication, treatment compliance, and overall quality of life. And, from a neurological perspective, cytokine-induced cognitive disturbance during systemic inflammatory processes may be part of the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease. In previous work, the PI developed an animal model to assess the degree to which proinflammatory cytokines disturb information processing during the course of bacterial infection. This proposal represents a replication and extension of this work. Experiments will be conducted that examine the effect of five cytokines: interleukin-1-alpha (IL1alpha, interleukin-1- beta (IL1beta), interleukin-6 (IL6), interferon-alpha (IFNalpha), and tumor necrosis factor-alpha (TNFalpha). In each of the first five experiments, one of the five cytokines will be tested (relative to saline- injected controls) for its effect on spatial learning. Also a second treatment group will receive cytokine plus a cocktail of anti-cytokine antibodies designed to neutralize a set of endogenous cytokines that may be elicited by the exogenous cytokine treatment. This antibody treatment will be pre-tested to ensure that it is behaviorally inert. A sixth experiment will begin the description of neurochemical mediators of cytokine-induced visual learning deficit. The cyclo-oxygenase inhibitor, indomethacin, will be used to block the production of prostaglandins, which have been shown to mediate a number of behavioral and physiological effects of cytokines. Future experiments will pair intraperitoneal injections of cytokines with intracerebroventricular injections of various neurochemical antagonists, a model that will help delineate the CNS systems involved in cognitive responses to systemic illness. Data generated by the proposed project will help guide this research program.